Project 3: Synthesis and Optimization of Selective a4B2 nAChR Desensitizers According to the United States National Institute on Drug Abuse, abuse and addiction to alcohol, nicotine, and illegal substances cost Americans upwards of half a trillion dollars a year, considering their combined medical, economic, criminal, and social impact. Every year, abuse of illicit drugs and alcohol contributes to the death of more than 100,000 Americans, while tobacco is linked to an estimated 440,000 deaths per year. With this in mind, there is a great need to develop new therapeutics for drug abuse and addictions. In this grant we will use medicinal chemistry to design, synthesize and optimize desensitizers of a4B2 nAChR based structure activity relationships for Sazetidine A analogues. In this application, we present a new class of a4B2 desensitizers called Triazetidines and propose the optimization both in vitro and in vivo. We will also provide gram scale synthetic support for all optimized candidates in vivo behavioral evaluation (project 2) and acute toxicity studies (project 3). This will allow us to establish a therapeutic index for the candidate compounds in this proposal.